1. Field of the Invention
This invention relates to a method of increasing alertness in an individual by administering an effective amount of an alertness-increasing Vomeropherin to the individual; and to an alarm device that, when activated, emits an alertness-increasing vomeropherin. The method and device are especially useful in increasing alertness in individuals who are not readily responsive to external stimuli.
2. Background Information
Fire and smoke alarms are designed to alert the occupants of a building of the development of a fire. In recent years, they have been considered an essential life-saving device and have become a standard feature in most homes and commercial buildings. Most of the home fire alarms currently on the market produce an audible signal to warn and/or awaken individuals who are in the vicinity of a developing fire. Some fire alarms also produce visible signals such as flashing lights.
Carbon monoxide alarms are designed to alert the occupants of a building of carbon monoxide gas in the atmosphere of the building. They are becoming more popular for home use, since carbon monoxide cannot be detected by an unaided individual (the gas is colorless and odorless), and is the product of incomplete combustion and may be the product, for example, of either fire or, more commonly, a malfunctioning gas appliance such as a furnace. These alarms also typically produce an audible signal, and may also produce a visible signal.
Alarms may also be used to indicate the presence of other alarm conditions, which include but are not limited to, presence of radon (a tasteless, odorless, and invisible gas), propane gas, methane, apnea (suspension of respiration), or unauthorized entry (for burglar alarms).
Alarms may also be used to indicate the presence of an alarm condition (generally, in a non-hazardous situation) in which there is a request for an individual to respond, such as a ringing phone (request for the individual to answer the phone), a buzzing or ringing alarm clock (request for the individual to awaken), a ringing doorbell (request for the individual to answer the door), and the like.
However, for individuals who have a tendency to sleep deeply, whether normally, because of a sleeping disorder, because of drug- or alcohol-induced sleepiness, or because of conditions such as anosmia (lack of sense of smell), healing impairment, or blindness, the usual stimuli (either direct hazard-related stimuli such as the presence of smoke, or stimuli from alarm systems) may be ineffective in warning them of the alarm condition and enabling them to take appropriate action.
It is therefore desirable to develop a method of increasing the alertness of an individual. It is also desirable to develop an alarm device that would increase the alertness of an individual in the presence of an alarm condition, to enable the individual to respond more effectively to the alarm condition.
In a first aspect, this invention provides a method of increasing alertness in an individual, comprising administering to the vomeronasal organ (VNO) of that individual an alertness-increasing effective amount of a compound of the formula: 
where:
R1 is hydrogen, C1-5 alkanoyl, or xe2x80x94SO1H or a salt thereof,
R2 is hydrogen or methylene;
R3 is hydrogen or C1-4 alkyl;
one or two non-adjacent members of xe2x80x9caxe2x80x9d, xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d, and xe2x80x9cdxe2x80x9d are optional double bonds; and
when R2 is hydrogen, xe2x80x9cexe2x80x9d is either a double bond or a 16xcex1, 17xcex1-epoxide, and
when R2 is methylene xe2x80x9cexe2x80x9d is absent and xe2x80x9cfxe2x80x9d is a double bond.
In a second aspect, this invention provides an alarm device for alerting an individual to the presence of an alarm condition, comprising:
(a) a detector for the presence of the alarm condition, and
(b) a dispenser for administering to the vomeronasal organ of the individual an alertness-increasing effective amount of a compound of the formula: 
xe2x80x83where:
R1 is hydrogen, C1-5 alkanoyl, or xe2x80x94SO3H or a salt thereof;
R2 is hydrogen or methylene;
R3 is hydrogen or C1-4 alkyl;
one or two non-adjacent members of xe2x80x9caxe2x80x9d, xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d, and xe2x80x9cdxe2x80x9d are optional double bonds; and
when R2 is hydrogen xe2x80x9cexe2x80x9d is either a double bond or a 16xcex1, 17xcex1-epoxide, and
when R2 is methylene, xe2x80x9cexe2x80x9d is absent and xe2x80x9cfxe2x80x9d is a double bond; and, optionally,
(c) a warning means.
Unless otherwise stated; the following terms used in the specification and claims have the meaning given below.
xe2x80x9cAlertnessxe2x80x9d includes wakefulness and responsiveness to external stimuli. Thus, xe2x80x9cincreasing alertness in an individualxe2x80x9d includes either or both of awakening that individual and increasing that individual""s responsiveness to an external stimulus, an effect that may take place with lightening of a state of sleep but without full awakening. Thus, increasing alertness in an individual would mean increasing the responsiveness of that individual to external stimuli, such as a bell ringing, phone ringing, fire, smoke, and the like.
An xe2x80x9calarm conditionxe2x80x9d with respect to an individual is one in which the safety or health of that individual or others may be adversely affected by the lack of a response by that individual, or one in which there is a request for an individual to respond. Exemplary alarm conditions in which the safety or health of that individual or others may be adversely affected by the lack of a response by that individual include fire, smoke, toxic gas (such as carbon monoxide), unauthorized entry (e.g. into the individual""s residence), and the like. Exemplary alarm conditions in which the safety or health of others may be adversely affected by the lack of response include the conditions listed above and others such as, for example, apnea (such as of a sleeping infantxe2x80x94baby monitors are commercially available to warn parents of such an occurrence). It also includes conditions in which an ailing person (such as a person with pulmonary or cardiovascular disease) may require immediate assistance and may summon assistance with a xe2x80x9ccall buzzerxe2x80x9d or the like, particularly in a home health setting where the responding individual may not remain awake all night. Exemplary alarm conditions in which there is request for an individual to respond (generally, in non-hazardous situations) include, a buzzing alarm clock (request for an individual to awaken), a ringing phone (request to answer the phone), a ringing door bell (request to answer the door), and the like. An xe2x80x9calarmxe2x80x9d or xe2x80x9calarm devicexe2x80x9d for such alarm conditions therefore includes not only an alarm in which the alarm condition is detected by detection of the presence of a condition in which the safety or health of that individual or others may be adversely affected by the lack of a response by that individual, but also by the detection of a condition in which there is a request for the individual to respond.
xe2x80x9cC1-4 Alkylxe2x80x9d refers to a cyclic, branched or straight chain monovalent hydrocarbon radical of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, cyclopropyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, and cyclopropylmethyl.
xe2x80x9cC1-5 Alkanoylxe2x80x9d refers to the group xe2x80x94C(O)xe2x80x94R where R is hydrogen or C1-4 alkyl.
An xe2x80x9ceffective amountxe2x80x9d refers to an amount sufficient to increase the alertness of an individual.
A xe2x80x9cvomeropherinxe2x80x9d is a compound that functions as a chemosensory messenger, binds to a specific vomeronasal neuroepithelial receptor, and induces a physiological or behavioral effect. The effect of a xe2x80x9cvomeropherinxe2x80x9d is mediated through its interaction with the vomeronasal organ (VNO).
The transitional term xe2x80x9ccomprisingxe2x80x9d is an open-ended term synonymous with xe2x80x9cincludingxe2x80x9d and does not exclude additional unrecited elements.
The alertness-increasing vomeropherins usable in this invention are compounds of the formula: 
where:
R1 is hydrogen, C1-5 alkanoyl, or xe2x80x94SO3H or a salt thereof;
R2 is hydrogen or methylene;
R3 is hydrogen or C1-4 alkyl;
one or two non-adjacent members of xe2x80x9caxe2x80x9d, xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d, and xe2x80x9cdxe2x80x9d are optional double bonds; and
when R2 is hydrogen, xe2x80x9cexe2x80x9d is either a double bond or a 16xcex1, 17xcex1-epoxide, and
when R2 is methylene, xe2x80x9cexe2x80x9d is absent and xe2x80x9cfxe2x80x9d is a double bond.
The 13-position in these compounds is a chiral center, and the 13-methyl has the xcex2 configuration. When both xe2x80x9caxe2x80x9d and xe2x80x9cbxe2x80x9d are absent and R3 is C1-4 alkyl, the 7-position is also a chiral center, and the 7-alkyl has the a configuration.
A preferred vomeropherin is a compound of the formula above where R1 is acetyl, R2 and R3 are hydrogen, xe2x80x9ca xe2x80x9d, xe2x80x9cbxe2x80x9d, xe2x80x9ccxe2x80x9d and xe2x80x9cdxe2x80x9d are absent, and xe2x80x9cexe2x80x9d is a double bond, namely estra-1,3,5(10),16-tetraen-3-yl acetate.
Another preferred vomeropherin is a compound of the formula wherein R1 is hydrogen, R2 is methylene, R3 is absent, xe2x80x9caxe2x80x9d, xe2x80x9ccxe2x80x9d and xe2x80x9cfxe2x80x9d are present and xe2x80x9cbxe2x80x9d and xe2x80x9cdxe2x80x9d are absent, namely, 17-methylene-1,3,5(10),6,8-pentaen-3-ol.
The vomeropherins useful in this invention may be prepared following the general procedures for the synthesis of steroids which are well-known to those skilled in the art (see for example, Fieser, L. F. and M. Fieser, Steroids, Reinhold, New York, 1959). The specific reaction conditions may be determined by routine experimentation.
Estra-1,3,5(10),16-tetraen-3-ol, for example, may be prepared from estrone (estra-1,3,5(10)-trien-3-ol-17-one) by reacting estrone with an appropriate amount of p-toluenesulfonylhydrazide in a polar solvent such as dry methanol or ethanol under reflux to form the corresponding estrone p-toluenesulfonylhydrazone. The estrone p-toluenesulfonylhydrazone is then reacted with n-butyl lithium in an inert aprotic solvent such as dry tetrahydrofuran, ether, dimethoxyethane or the like to give estra-1,3,5(10),16-tetraen-3-ol.
Acyl derivatives of estra-1,3,5(10),16-tetraen-3-ol are prepared by conventional means, for example, by treatment with an appropriate anhydride in ether/pynidine at room temperature.
The compound of formula wherein R2 is hydrogen and xe2x80x9cexe2x80x9d is a 16xcex1, 17xcex1-epoxide may be prepared according to the method as demonstrated in Example 3 below.
The salts of the compounds where R1 is xe2x80x94SO3H may include metallic salts such as sodium, potassium, lithium salts and the like. The synthetic procedure for the salts is, specifically demonstrated in Example 4 below. The salt derivatives have the advantage that they crystallize and solubilize readily.
Purification of the products is accomplished by means of chromatography and/or crystallization, as known to those skilled in the art.
These vomeropherins have a psychostimulant effect including a primary arousing effect, evidenced by decreased total sleep time and increased sleep onset latency. They also increase an individual""s alertness to external stimuli, such as stimuli associated with the presence of alarm conditions, e.g., fire, smoke, audible or visible alarms.
They have an alertness-increasing effect in normal individuals; however, they are expected to be particularly useful in individuals who have a tendency to sleep deeply, whether normally, because of a sleeping disorder, because of drug- or alcohol-induced sleepiness, or because of conditions such as anosmia (lack of sense of smell), hearing impairment, or blindness, that makes them less responsive to stimuli, especially the usual stimuli associated with hazardous conditions.
1) Vomeronasal Organ (VNO)
The present invention involves a non-systemic delivery of an alertness-increasing vomeropherin to the VNO. Delivery provides for contacting neurochemical receptors in the VNO, also known as xe2x80x9cJacobson""s organ,xe2x80x9d with such vomeropherin. The VNO is a small bilateral nasal organ with a central lumen and a pit opening to the nasal cavity. The lumen is lined with sensory neuroepithelia which constitute a distinct locus of chemosensory receptors. The chemosensory cells of the VNO neuroepithelia form the vomeronasal nerve and have direct input to the cortico-medial amygdaloid basal forebrain and hypothalamic nuclei of the brain. The distal axons of terminalis nerve neurons may also serve as neurochemical receptors in the VNO.
2) Compositions and Methods of Delivery
The vomeropherins of this invention are administered to individuals through emission into the environment.
These vomeropherins may be emitted into the environment by an aerosol dispenser, (intended for spraying into large enclosed areas), using a propellant gas to deliver the vomeropherin as a fine spray or mist. A typical dispenser contains a suspension or solution of the vomeropherin admixed with a liquefied gas propellant, or with a combination of water, ethanol, and a propellant. The propellant may be one or more gases such as chlorofluorocarbons (CFCs) or other non-CFC gases that are non-toxic and non-flammable. The propellant must also be volatile so that when the propellant is released in the air it evaporates leaving only the alertness-increasing vomeropherin. An aerosol dispenser where non-liquefied pressurized gas propellants are in a separate chamber from the aerosol solution (containing the vomeropherin) can also be used. Examples of possible propellants include nitrogen, carbon dioxide, and nitrous oxide.
When delivered through the use of an aerosol, unless dissolved, the compound is present in finely and uniform divided form. Typical percentages of the compound present in the aerosol composition are 0.001 to 2% by weight, preferably 0.004 to 0.10%.
The aerosol composition may also contain a surfactant. Suitable surfactants must, of course, be nontoxic and preferably soluble in the propellant. Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, and hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark xe2x80x9cSpansxe2x80x9d) and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides, may also be employed. The preferred surfactants are sorbitan oleates, e.g., those sold under the trademarks xe2x80x9cArlacel Cxe2x80x9d (sorbitan sesquioleate), xe2x80x9cSpan 80xe2x80x9d (sorbitan monoleate) and xe2x80x9cSpan 85xe2x80x9d (sorbitan trioleate). The surfactant may constitute 0.1-20% by weight of the composition, preferably 0.25-5%.
In producing the aerosol, a container equipped with a suitable valve is filled with an appropriate propellant, the finely divided compound and optionally a surfactant. The ingredients are maintained at an elevated pressure until released.
When the vomeropherins are delivered as a vapor, the delivery means are well known to those skilled in the art of neurophysiology (for example, Tucker, D. and T. Shibuya, Cold Spring Harbor Symp. Quant. Biol. (1965) 30:207 and Vigouroux, M., et al, (J. Neurosci. Methods (1988) 24:57).
In a basic form, a vapor delivery means is a constant air flow source bubbled through a liquid medium. These vomeropherins may also be impregnated in a material (preferably with a weight ratio of 1/30) such as a sponge or cotton in a dry powdered or crystalline form for delivery as a vapor. The vapor may be regulated by a single parameter or in combinationxe2x80x94for instance, purity, temperature, water vapor tension, flow rate, and the like. Various stimulants for instance an odorant, a flavoring, a drug, or the like, may be introduced into the vapor stream either continuously, or preferably, as a pulse of particular duration. The crystals when delivered must be of uniform size with no large clumps.
These vomeropherins may also be formulated into a liquid composition such as a solution which is sprayed into the environment. In this case, a variety of non-toxic and non-inflammable solvents or solvent mixtures which are capable of dissolving the vomeropherins are suitable, for example, ethanol, propylene glycol and DMSO (dimethyl sulfoxide). Usually an aqueous ethanol solvent is preferred. The preferred concentration of the ethanol in the mixture is in the range of 1 to 4% (v/v). However since the solution is not administered directly to the nasal passage, an aqueous ethanol solvent with a higher. concentration of the ethanol would also be acceptable.
The concentrations of the vomeropherins in the compositions described above may vary. However they must be sufficiently high to deliver, when emitted into the environment, an effective amount of the compound to the individuals.
3) Effective Dose Level
The vomeropherins of this invention are effective in increasing alertness in both male and female, although there may be gender variations in the dose levels at which the compounds are effective, the dose range is 0.1 ng/100 xcexcl to 100 xcexcg/100-xcexcl. A single administration of at least about 200 picograms, delivered directly into the lumen of the VNO, is effective in eliciting a transient autonomic response. When administered to the nasal cavity, the amount is about 100 picograms to about 100 micrograms, preferably about 1 nanogram to about 10 micrograms, more preferably about 10 nanograms to about 1 nicrogram.
The doses will be as above if the dose is to be administered by a device directly to the individual""s VNO or nose. If the dose, however, is to be administered providing a sufficient concentration of the vomeropherin in the air surrounding the individual(s), so that it contacts the individual(s)""s VNO by inhalation through the nose or diffusion into the nasal cavity, then the quantity of the vomeropherin to be dispersed to achieve that dose will be substantially higher depending on factors such as the individual being alerted, the number of individuals in the room, the size of the room, and the placement of the dispenser.
For example, considering that humans at rest on average displace 4 liters of air per minute, a dispenser containing 100 mg of vomeropherin is sufficient to saturate a volume of 25 cubic meters, the approximate volume of a 9ft.xc3x9712 ftxc3x978 ft room; and a dispenser containing 8 mg of vomeropherin is sufficient to saturate a volume of 2 cubic meters, such as when the dispenser is mounted on the headboard of a bed. Even if the room has continuous air flow, the loss of vomeropherin in the air will be negligible.
Thus, a person of ordinary skill in the art, with the skill and this disclosure, can calculate the appropriate total quantity required to achieve an alertness-increasing effective amount in individuals.
A typical alarm device (whether for hazardous and non-hazardous situations) consists of a detector to sense the presence of an alarm condition (such as, but not limited to, presence of fire, smoke, unauthorized entry, or request to answer the phone), and one or more warning means, such as a horn or a flashing light, to generate an alarm signal. A detector in a smoke alarm, for example, senses the presence of smoke, through photoelectric or ionization means. Once the detector senses the presence of smoke, an electric signal is sent to the sounder auxiliary relay activating the warning means, such as a horn, thus generating an alarm signal.
There are typically two types of smoke alarms. Ionization smoke alarms use an ionization chamber, which consists of two plates with a voltage across them, along with a radioactive source of ionizing radiation, generally a very small amount of americium-241. The detector operates by measuring the change in ionization caused by smoke entering the chamber.
Photoelectric smoke alarms, on the other hand, use light and a light detector to sense a developing fire. In a normal condition, the light from the light source shoots straight across and misses the detector. Smoke particles, however, scatter the light and, consequently, some amount of light hits the detector activating the warning means, such as a horn.
A detector in a carbon monoxide (CO) alarm measures levels of CO over time. It may be a higher amount of CO over a short period of time or a lower amount for an extended time frame. In either case, when the detector senses a certain saturation level of CO, an electric signal is sent triggering the horn.
Using the detectors of alarm devices, such as, but not limited to, detectors for smoke, carbon monoxide, unauthorized entry, call connection, or pressed door bell, an alarm device of the present invention can be made comprising of a detector sensing the alarm condition and a dispenser containing the alertness-increasing vomeropherin. Waning means producing an audible and/or visible signal, such as a horn or a light, may also be incorporated into the alarm device.
The dispenser may, be contained within or outside the alarm device. The dispenser, in practice, is preferably placed in allocation which is near the individual, for example near the bed of the individual to allow the vomeropherin to be received by the individual more readily.
In any case, once the detector senses the alarm condition, the dispenser is activated to release the alertness-increasing vomeropherin, thereby increasing the alertness of individuals. The other warning means, if present, are also activated.